Injectable long-acting human immunodeficiency virus antiretroviral prodrugs with improved pharmacokinetic profiles.

Autor: Krovi SA; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Gallovic MD; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Keller AM; Department of Microbiology, Ohio State University, Columbus, OH 43210, USA., Bhat M; Department of Microbiology, Ohio State University, Columbus, OH 43210, USA., Tiet P; United Therapeutics, Durham, NC 27709, USA., Chen N; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Collier MA; Avanti Polar Lipids, Alabaster, AL 35007, USA., Gurysh EG; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Pino EN; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Johnson MM; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Shamim Hasan Zahid M; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Cottrell ML; Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Pirone JR; Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Kashuba AD; Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Kwiek JJ; Department of Microbiology, Ohio State University, Columbus, OH 43210, USA., Bachelder EM; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA., Ainslie KM; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA. Electronic address: ainsliek@email.unc.edu.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2018 Dec 01; Vol. 552 (1-2), pp. 371-377. Date of Electronic Publication: 2018 Oct 08.
DOI: 10.1016/j.ijpharm.2018.10.017
Abstrakt: While highly active antiretroviral therapy (HAART) has significantly reduced mortality rates in patients with human immunodeficiency virus type 1 (HIV-1), its efficacy may be impeded by emergence of drug resistance caused by lack of patient adherence. A therapeutic strategy that requires infrequent drug administration as a result of sustained release of antiretroviral drugs would put less burden on the patient. Long-acting antiretroviral prodrugs for HIV therapy were synthesized through modification of the active drugs, emtricitabine (FTC) and elvitegravir (EVG), with docosahexaenoic acid (DHA) in one-step, one-pot, high-yielding reactions. The in vitro drug release profiles of these synthetic conjugates demonstrated sustained and controlled release of the active drug over a period of 3-4 weeks attributable to the hydrolysis of the chemical linker in conjunction with the hydrophilicity of the parent drug. Both conjugates exhibited superior antiviral activities in tissue culture models of HIV replication as compared to those of the free drugs, strengthening their role as potent prodrugs for HIV therapy. Pharmacokinetic analysis in CD1 mice further confirmed the long-acting aspect of these conjugates with released drug concentrations in plasma detected at their respective IC 90 /IC 95 values over a period of 2 weeks and discernable amounts of active drug even at 6 weeks. Our findings suggest that the injectable small molecule conjugates could be used as long-acting controlled release of FTC and EVG in attempts to mitigate adherence-related HIV resistance.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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